PROJECT SUMMARY Despite the substantial work in cardiovascular pharmacogenomics published over the past decade, a fundamental gap remains in understanding whether the genomic diversity of Caribbean Hispanics accounts for high inter-individual variability of clinical outcomes to preventive dual antiplatelet therapy (DAPT) with clopidogrel. Caribbean Hispanics are disproportionately affected by cardio-metabolic disorders, but with a limited expectation of benefits from existing genomic-based algorithms. We will focus on clopidogrel to develop urgently-needed genomic-driven prescription guidelines for this population. To this purpose, we propose to perform the first ever GWAS of a pharmacogenetically actionable prescription drug in Caribbean Hispanics. Our proposal will also take a novel approach to definitively assess the admixture component and is also highly practical for the development of a clinical decision support (CDS) tool. We will implement a treatment algorithm to guide DAPT in Caribbean Hispanics and will create a repository of genomic DNAs and fully annotated clinical and genomic dataset from Caribbean Hispanics with cardiovascular diseases. Shaped by strong preliminary data, we will test the following hypothesis: There are unknown genetic variants that uniquely contribute to clopidogrel responsiveness in Caribbean Hispanics to such extent that a developed CDS tool that incorporates personal ethno-specific genotypes and ex vivo pharmacodynamic (PD) testing will help enable more precise recommendations for optimizing medical outcomes to antiplatelet therapy in this population. The study will be conducted over 5 years in 1,000 cardiovascular patients treated with clopidogrel for secondary prevention of thromboembolic events. It is expected that this study advances the adoption of a Precision Medicine (PM) paradigm for the benefit of Hispanic patients. The richer genetic variance in Latinos is likely to contribute substantially to variability in response to drug treatments, a component that will be missed by traditional studies in homogeneous populations. This addressable oversight is of great concern, since it will tend to exacerbate the healthcare disparity already experienced by Hispanic populations in the US. Hispanics have been largely excluded from PM initiatives, which increase dramatically the disparities in translating benefits from new findings in pharmacogenomics to this medically underserved population, exacerbating the existing inequity in healthcare services. Accordingly, the proposed research will expand our current understanding on the pharmacogenomics of clopidogrel. Advancing knowledge in the under-investigated area of pharmacogenetics in minority populations will generate results that apply to personalize DAPT in the wider population as it moves, inevitably, toward increasing heterogeneity through admixed genomes.